Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof

Abstract

Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases due to mutations in Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

1. A compound or pharmaceutically acceptable salt thereof having the structure of formula Ia: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2 , R 4 , R 6 , R 7 , R 8  and R 9  are independently selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , —(C 1-9  alkyl) n carbocyclylR 13 , —(C 1-9  alkyl) n heterocyclylR 13 , —(C 1-9  alkyl) n arylR 13 , —(C 1-9  alkyl) n heteroarylR 13 , —(C 1-9  alkyl) n OR 10 , —(C 1-9  alkyl) n SR 10 , —(C 1-9  alkyl) n S(═O)R 11 , —(C 1-9  alkyl) n SO 2 R 10 , —(C 1-9  alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9  alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9  alkyl) n CO 2 R 10  and —(C 1-9  alkyl) n C(=A)R 10 ; 
         R 3  is selected from the group consisting of —NRS(═O)R 14 , —(C 1-9 alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15  and-heteroarylR 14 R 15 ; 
         alternatively, one of each R 1  and R 2 , R 2  and R 3 , R 3  and R 4 , R 6  and R 7 , R 7  and R 8  or R 8  and R 9  are taken together to form a ring which is selected from the group consisting of aryl, heteroaryl, 
       
       
         
           
           
               
               
           
         
         wherein each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond; 
         each R 10  is independently selected from the group consisting of H, —C 1-9  alkyl, —CF 3 , —(C 1-9  alkyl) n carbocyclyl, —(C 1-9  alkyl) n heterocyclyl, —(C 1-9  alkyl) n aryl and —(C 1-9  alkyl) n heteroaryl; 
         each R 11  is independently selected from the group consisting of —C 1-9  alkyl, —CF 3 , —(C 1-9  alkyl) n carbocyclyl, —(C 1-9  alkyl) n heterocyclyl, —(C 1-9  alkyl) n aryl and —(C 1-9  alkyl) n heteroaryl; 
         each R 12  is independently selected from the group consisting of —OR 10  and R 10 ; 
         each R 13  is 1-5 substituents each selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , carbocyclyl, heterocyclyl, aryl, heteroaryl, —(C 1-9  alkyl) n OR 10 , —(C 1-9  alkyl) n SR 10 , —(C 1-9  alkyl) n S(═O)R 11 , —(C 1-9  alkyl) n SO 2 R 10 , —(C 1-9  alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9  alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9  alkyl) n CO 2 R 10  and —(C 1-9  alkyl) n C(=A)R 10 ; 
         R 14  is selected from the group consisting of —NR 10 )C(=A)R 10 —NR 10 S(═O)R 11 , —NR 10 SO 2 R 10 , —NR 10 C(═O)N(R 16 ) 2 ,)—NR 10 C(═S)N(R 10 ) 2 , —NR 10 C(═NR 12 )N(R 10 ) 2 , —N(R 16 ) 2 , —C(═O)NR 10 R 17 , —C(═S)N(R 10 ) 2 , —C(═NR 12 )N(R 10 ) 2 , —OC(=A)R 10 , —C(=A)R  10 , —NR 10 C(=A)OR 10  and —OC(=A)NR 10 R 10 ; 
         R 15  is 1-4 substituents each selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , carbocyclylR 13 , heterocyclylR 13 , arylR 13 , heteroarylR 13 , —(C 1-9  alkyl) n OR 10 , —(C 1-9  alkyl) n SR 10 , —(C 1-9  alkyl) n S(═O)R 11 , —(C 1-9  alkyl) n SO 2 R 10 , —(C 1-9  alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9  alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9  alkyl) n CO 2 R 10  and —(C 1-9  alkyl) n C(=A)R 10 ; 
         R 16  is —C 1-9  alkyl; 
         each R 17  is independently selected from the group consisting of -heterocyclylR 13 , —(C 1-9  alkyl)heterocyclylR 13  and —(C 1-9  alkyl)carbocyclylR 13 ; 
         R 18  and R 19  are independently selected from the group consisting of H, C 1-9  alkyl, halide, —(C 1-9  alkyl) n carbocyclylR 13 , —(C 1-9  alkyl) n heterocyclylR 13 , —(C 1-9  alkyl) n arylR 13 , —(C l-9  alkyl) n heteroarylR 13 , —(C 1-9  alkyl) n OR 10 , —(C 1-9  alkyl) n SR 10 , —(C 1-9  alkyl) n S(═O)R 11 , —(C 1-9  alkyl) n SO 2 R 10 , —(C 1-9  alkyl) n N(R 10 )SO 2 R 10 , —(C 1-9  alkyl) n SO 2 N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n C(=A)N(R 10 ) 2 , —(C 1-9  alkyl) n N(R 10 )C(=A)R 10 , —NO 2 , —CN, —(C 1-9  alkyl) n CO 2 R 10  and —(C 1-9  alkyl) n C(=A)R 10 ; 
         alternatively, R 18  and R 19  are taken together to form a ring which is selected from the group consisting of benzene and pyridine; 
         each A is independently selected from O, S and NR 12 ; 
         Y 1 , Y 2 , and Y 4  are C; 
         Y 3  is nitrogen and R 8  is absent; and 
         each n is 0 or 1. 
       
     
     
       2. The compound of  claim 1  wherein n is 0. 
     
     
       3. The compound of  claim 1  wherein n is 1. 
     
     
       4. The compound of  claim 1  wherein A is O. 
     
     
       5. The compound of  claim 1  wherein R 1 , R 2  and R 4  are H and R 3  is independently selected from the group consisting of —NRS(═O)R 14 , —(C 1-9  alkyl)R 14 , -carbocyclylR 14 R 15 , -heterocyclylR 14 R 15 , -arylR 14 R 15  and -heteroarylR 14 R 15 . 
     
     
       6. The compound of  claim 5  wherein R 3  is —(C 1-9 alkyl)R 14 . 
     
     
       7. The compound of  claim 5  wherein R 3  is -carbocyclylR 14 R 15 . 
     
     
       8. The compound of  claim 5  wherein R 3  is -heterocyclylR 14 R 15 . 
     
     
       9. The compound of  claim 5  wherein R 3  is -arylR 14 R 15 . 
     
     
       10. The compound of  claim 5  wherein R 3  is -heteroarylR 14 R 15 . 
     
     
       11. The compound of  claim 10  wherein R 14  is —NR 10 C(=A)R 10  and A is O. 
     
     
       12. The compound of  claim 10  wherein R 14  is —C(═O)NR 10 R 17 . 
     
     
       13. The compound as in any of  claims 10 - 12 , in which the heteroaryl is a pyridine. 
     
     
       14. The compound as in any of  claims 10 - 11 , in which R 14  is —NHC(═O)R 10  and R 10  is selected from the group consisting of —C 1-9  alkyl, carbocyclyl, aryl and —(C 1-9  alkyl)aryl. 
     
     
       15. The compound as in any of  claims 10  and  12 , in which R 14  is —C(═O)NHR 17 , R 17  is —(C 1-9  alkyl)carbocyclylR 13  and R 13  is H. 
     
     
       16. The compound of  claim 1  wherein Y 3  is nitrogen and R 8  is absent. 
     
     
       17. The compound of  claim 16  wherein R 6  is —(C 1-9  alkyl) n heteroarylR 13 , n is 0 and R 13  is H. 
     
     
       18. The compound of  claim 1  having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       19. A pharmaceutical composition comprising a therapeutically effective amount of compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
       20. The compound of  claim 1 , wherein R 1 , R 2 , R 4 , R 7 , and R 9  are H; R 3  is heteroarylR 14 R 15 ; and R 6  is —(C 1-9  alkyl) n arylR 13 . 
     
     
       21. The compound of  claim 20 , wherein R 13  is halide. 
     
     
       22. The compound of  claim 21 , wherein the halide is fluoro. 
     
     
       23. The compound of  claim 1  having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       24. The compound of  claim 1  having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.